Opioid depot formulations

ABSTRACT

The present invention relates to pre-formulations comprising low viscosity, non-liquid crystalline, mixtures of:
     a) at least one neutral diacyl lipid and/or at least one tocopherol;   b) at least one phospholipid;   c) at least one biocompatible, oxygen containing, low viscosity organic solvent;
 
wherein at least one opioid bioactive agent is dissolved or dispersed in the low viscosity mixture and wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid. The preformulations are suitable for generating parenteral, non-parenteral and topical depot compositions for sustained release of active agents. The invention additionally relates to a method of delivery of an active agent comprising administration of a preformulation of the invention, a method of treatment comprising administration of a preformulation of the invention and the use of a preformulation of the invention in a method for the manufacture of a medicament. The method of treatments is especially for opioid addiction, dependence and/or withdrawal.

This application is a continuation-in-part of U.S. application Ser. No.11/628,007 filed Jul. 24, 2007, which in turn is the US national phaseof international application PCT/GB2005/002217, filed 6 Jun. 2005, whichdesignated the U.S. and claims priority of GB 0412530.8, filed 4 Jun.2004; GB 0500807.3, filed 14 Jan. 2005 and GB 0507811.8, filed 18 Apr.2005, the entire contents of each of which are hereby incorporated byreference.

The present invention relates to formulation precursors(pre-formulations) for the in situ generation of controlled releaselipid compositions. In particular, the invention relates topre-formulations in the form of low viscosity mixtures (such asmolecular solutions) of amphiphilic components and at least onebioactive agent which undergo at least one phase transition uponexposure to aqueous fluids, such as body fluids, thereby forming acontrolled release matrix which optionally is bioadhesive.

Many bioactive agents including pharmaceuticals, nutrients, vitamins andso forth have a “functional window”. That is to say that there is arange of concentrations over which these agents can be observed toprovide some biological effect. Where the concentration in theappropriate part of the body (e.g. locally or as demonstrated by serumconcentration) falls below a certain level, no beneficial effect can beattributed to the agent. Similarly, there is generally an upperconcentration level above which no further benefit is derived byincreasing the concentration. In some cases increasing the concentrationabove a particular level, results in undesirable or even dangerouseffects.

Some bioactive agents have a long biological half-life and/or a widefunctional window and thus may be administered occasionally, maintaininga functional biological concentration over a substantial period of time(e.g. 6 hours to several days). In other cases the rate of clearance ishigh and/or the functional window is narrow and thus to maintain abiological concentration within this window regular (or even continuous)doses of a small amount are required. This can be particularly difficultwhere non-oral routes of administration (e.g. parenteral administration)are desirable. Furthermore, in some circumstances, such as in thefitting of implants (e.g. joint replacements or oral implants) the areaof desired action may not remain accessible for repeated administration.In such cases a single administration must provide active agent at atherapeutic level over the whole period during which activity is needed.

Various methods have been used and proposed for the sustained release ofbiologically active agents. Such methods include slow-release, orallyadministered compositions, such as coated tablets, formulations designedfor gradual absorption, such as transdermal patches, and slow-releaseimplants such as “sticks” implanted under the skin.

One method by which the gradual release of a bioactive agent has beenproposed is a so-called “depot” injection. In this method, a bioactiveagent is formulated with carriers providing a gradual release of activeagent over a period of a number of hours or days. These are often basedupon a degrading matrix which gradually disperses in the body to releasethe active agent.

The most common of the established methods of depot injection reliesupon a polymeric depot system. This is typically a biodegradable polymersuch poly (lactic acid) (PLA) and/or poly (lactic-co-glycolic acid)(PLGA) and may be in the form of a solution in an organic solvent, apre-polymer mixed with an initiator, encapsulated polymer particles orpolymer microspheres. The polymer or polymer particles entrap the activeagent and are gradually degraded releasing the agent by slow diffusionand/or as the matrix is absorbed. Examples of such systems include thosedescribed in U.S. Pat. No. 4,938,763, U.S. Pat. No. 5,480,656 and U.S.Pat. No. 6,113,943 and can result in delivery of active agents over aperiod of up to several months. These systems do, however, have a numberof limitations including the complexity of manufacturing and difficultyin sterilising (especially the microspheres). The local irritationcaused by the lactic and/or glycolic acid which is released at theinjection site is also a noticeable drawback. There is also often quitea complex procedure to prepare the injection dose from the powderprecursor

From a drug delivery point of view, polymer depot compositions also havethe disadvantage of accepting only relatively low drug loads and havinga “burst/lag” release profile. The nature of the polymeric matrix,especially when applied as a solution or pre-polymer, causes an initialburst of drug release when the composition is first administered. Thisis followed by a period of low release, while the degradation of thematrix begins, followed finally by an increase in the release rate tothe desired sustained profile. This burst/lag release profile can causethe in vivo concentration of active agent to burst above the functionalwindow immediately following administration, then drop back through thebottom of the functional window during the lag period before reaching asustained functional concentration. Evidently, from a functional andtoxicological point of view this burst/lag release profile isundesirable and could be dangerous. It may also limit the equilibriumconcentration which can be provided due to the danger of adverse effectsat the “peak” point.

Previous depot systems have been sought to address the problem of burstrelease. In particular, the use of hydrolysed polylactic acid and theinclusion of poly lactic acid-polyethylene glycol block copolymers havebeen proposed to provide the “low burst” polymeric system described inU.S. Pat. No. 6,113,943 and U.S. Pat. No. 6,630,115. These systemsprovide improved profiles but the burst/lag effect remains and they donot address other issues such as the irritation caused by the use ofpolymers producing acidic degradation products.

One alternative to the more established, polymer based, depot systemswas proposed in U.S. Pat. No. 5,807,573. This proposes a lipid basedsystem of a diacylglycerol, a phospholipid and optionally water,glycerol, ethylene glycol or propylene glycol to provide anadministration system in the reversed micellar “L₂” phase or a cubicliquid crystalline phase. Since this depot system is formed fromphysiologically well tolerated diacyl glycerols and phospholipids, anddoes not produce the lactic acid or glycolic acid degradation productsof the polymeric systems, there is less tendency for this system toproduce inflammation at the injection site. The liquid crystallinephases are, however, of high viscosity and the L₂ phase may also be tooviscous for ease of application. The authors of U.S. Pat. No. 5,807,573also do not provide any in vivo assessment of the release profile of theformulation and thus it is uncertain whether or not a “burst” profile isprovided.

The use of non-lamellar phase structures (such as liquid crystallinephases) in the delivery of bioactive agents is now relatively wellestablished. Such structures form when an amphiphilic compound isexposed to a solvent because the amphiphile has both polar and apolargroups which cluster to form polar and apolar regions. These regions caneffectively solubilise both polar and apolar compounds. In addition,many of the structures formed by amphiphiles in polar and/or apolarsolvents have a very considerable area of polar/apolar boundary at whichother amphiphilic compounds can be adsorbed and stabilised. Amphiphilescan also be formulated to protect active agents, to at least someextent, from aggressive biological environments, including enzymes, andthereby provide advantageous control over active agent stability andrelease.

The formation of non-lamellar regions in the amphiphile/water,amphiphile/oil and amphiphile/oil/water phase diagrams is a well knownphenomenon. Such phases include liquid crystalline phases such as thecubic P, cubic D, cubic G and hexagonal phases, which are fluid at themolecular level but show significant long-range order, and the L₃ phasewhich comprises a multiply interconnected bi-continuous network ofbilayer sheets which are non-lamellar but lack the long-range order ofthe liquid crystalline phases. Depending upon their curvature of theamphiphile sheets, these phases may be described as normal (meancurvature towards the apolar region) or reversed (mean curvature towardsthe polar region).

The non-lamellar liquid crystalline and L₃ phases are thermodynamicallystable systems. That is to say, they are not simply a meta-stable statethat will separate and/or reform into layers, lamellar phases or thelike, but are the stable thermodynamic form of the lipid/solventmixture.

While the effectiveness of known lipid depot formulations is high, thereare certain aspects in which the performance of these is less thanideal. In particular, cubic liquid crystalline phases proposed arerelatively viscous in nature. This makes application with a standardsyringe difficult and possibly painful to the patient, and makessterilisation by filtration impossible because the composition cannot bepassed through the necessary fine-pored membrane. As a result, thecompositions must be prepared under highly sterile conditions, adding tothe complexity of manufacturing. Where L₂ phases are used, these aregenerally of lower viscosity but these may still cause difficulty inapplication and allow access to only a small region of the phasediagram. Specifically, the solvents used in known lipid formulationshave only a limited effect in reducing the viscosity of the mixture.Water, for example, will induce the formation of a highly viscous liquidcrystalline phase and solvents such as glycerol and glycols have a highviscosity and do not provide any greatly advantageous decrease in theviscosity of the composition. Glycols are also typically toxic or poorlytolerated in vivo and can cause irritation when applied topically.

Furthermore, the known lipid compositions in the low-solvent L₂ phasemay support only a relatively low level of many bioactive agents becauseof their limited solubility in the components of the mixture in theabsence of water. In the presence of water, however, the formulationsadopt a highly viscous cubic liquid crystalline phase. It would be aclear advantage to provide a depot system that could be injected at lowviscosity and allowed release of the required concentration of bioactivewith a smaller depot composition volume.

The known lipid depot compositions also have practical access to onlycertain phase structures and compositions because other mixtures areeither too highly viscous for administration (such as those with highphospholipid concentrations) or run the risk of separation into two ormore separate phases (such as an L₂ phase in equilibrium with a phaserich in phospholipid). In particular, phospholipid concentrations above50% are not reachable by known methods and from the phase diagram shownin U.S. Pat. No. 5,807,573 it appears that the desired cubic phase isstable at no higher than 40% phospholipid. As a result, it has not beenpossible in practice to provide depot compositions of high phospholipidconcentration or having a hexagonal liquid crystalline phase structure.

One class of active agents having particular utility as depot orslow-release formulations are opioids. The term “Opioids” as used hereinencompasses a class of naturally occurring, semi-synthetic, and fullysynthetic compounds which show agonistic and/or antagonistic propertiesfor at least one opioid receptor. Opioids are of very great medicalvalue, being highly effective analgesics. They are typically used forpain relief after serious injuries and/or medical procedures and forthis use it can be of value to provide sustained dosing with a level orgently tapering concentration of active agent to correspond with ahealing and recovery profile over a number of days or weeks.

Unfortunately, tolerance to, and physiological dependence upon, opioidscan develop, and can lead to behavioural addiction, especially wherefast-acting opioids are used and/or the drugs are abused. Furthermore,abuse of opioids is common because of the euphoric effects which can becaused by their sudden administration. Withdrawal from opioids wheredependence has developed can be unpleasant, especially from fast-actingopioids which are commonly abused, such as diacetylmorphine (heroin) orfentanyl. One approach for assisting recovering addicts is thus totransfer them from fast-acting opioids to slower-acting drugs which canbe taken less frequently without causing the symptoms of withdrawal.Patients may then be provided with a maintenance level of theslower-acting opioid or gradually weaned from this by a gentlydecreasing dose regime.

Typical candidates for use as this slower-acting “opioid-replacement”drug are methadone and buprenorphine, and studies have shown that thesecan significantly reduce the chances of relapse in recovering addicts.One of the advantages of these opioids over the abused substances isthat they generally do not require administration so frequently in orderto avoid withdrawal symptoms. Methadone, for example, needs to beadministered daily, while the 37-hour half-life of buprenorphine meansthat a single dose is effective for 1-2 days, or longer in somepatients. Weekly patches of buprenorphine are also available, althoughat present these are for use in pain management rather than in curbingaddiction.

The two primary dosing methods for these slow-acting opioids inaddiction therapy are “detox”, in which a tapering dose is provided overa period of around 2 weeks, and “maintenance”, in which a level dose isprovided over a longer term of, typically, a few months. In both cases,and with any of the known opioid preparations, frequent administrationis generally required, which in turn requires on-going patientcompliance. Evidently, it would be a considerable advantage to provideslow-release formulations which could be administered infrequently, andwould provide a level, or gradually tapering, drug profile, to allowgradual detox or longer term maintenance without requiring frequentadministration.

The present inventors have now established that by providing apre-formulation comprising certain amphiphilic components, at least oneopioid bioactive agent and a biologically tolerable solvent, especiallyin a low viscosity phase such as molecular solution, the pre-formulationmay be generated addressing many of the shortfalls of previous depotformulations and allow the formation of an opioid depot product. Inparticular, the pre-formulation is easy to manufacture, may besterile-filtered, it has low viscosity (allowing easy and less painfuladministration), allows a high level of bioactive agent to beincorporated (thus allowing a smaller amount of composition to be used)and/or forms a desired non-lamellar depot composition in vivo having acontrollable “burst” or “non-burst” release profile. The compositionsare also formed from materials that are non-toxic, biotolerable andbiodegradable. Furthermore, the pre-formulation is suitable for theformation of depot compositions following parenteral administration andalso following non-parenteral (e.g. topical) administration to bodycavities and/or surfaces of the body or elsewhere.

In a first aspect, the present invention thus provides a pre-formulationcomprising a low viscosity mixture of:

a) at least one neutral diacyl lipid and/or a tocopherol;

b) at least one phospholipid;

c) at least one biocompatible, (preferably oxygen containing) organicsolvent;

wherein at least one opioid bioactive agent is dissolved or dispersed inthe low viscosity mixture and wherein the pre-formulation forms, or iscapable of forming, at least one liquid crystalline phase structure uponcontact with an aqueous fluid.

Generally, the aqueous fluid will be a body fluid such as fluid from amucosal surface, tears, sweat, saliva, gastro-intestinal fluid,extra-vascular fluid, extracellular fluid, interstitial fluid or plasma,and the pre-formulation will form a liquid crystalline phase structurewhen contacted with a body surface, area or cavity (e.g. in vivo) uponcontact with the aqueous body fluid. The pre-formulation of theinvention will generally not contain any significant quantity of waterprior to administration.

In a second aspect of the invention, there is also provided a method ofdelivery of an opioid bioactive agent to a human or non-human animal(preferably mammalian) body, this method comprising administering(preferably parenterally) a pre-formulation comprising a low viscositymixture of:

a) at least one neutral diacyl lipid and/or a tocopherol;

b) at least one phospholipid;

c) at least one biocompatible, (preferably oxygen containing) organicsolvent;

and at least one opioid bioactive agent is dissolved or dispersed in thelow viscosity mixture, whereby to form at least one liquid crystallinephase structure upon contact with an aqueous fluid in vivo followingadministration. Preferably, the pre-formulation administered in such amethod is a pre-formulation of the invention as described herein.

The method of administration suitable for the above method of theinvention will be a method appropriate for the condition to be treatedand the opioid bioactive agent used. A parenteral depot will thus beformed by parenteral (e.g. subcutaneous or intramuscular) administrationwhile a bioadhesive non-parenteral (e.g. topical) depot composition maybe formed by administration to the surface of skin, mucous membranesand/or nails, to opthalmological, nasal, oral or internal surfaces or tocavities such as nasal, rectal, vaginal or buccal cavities, theperiodontal pocket or cavities formed following extraction of a naturalor implanted structure or prior to insertion of an implant (e.g a joint,stent, cosmetic implant, tooth, tooth filling or other implant).

Since the key medicinal properties of opioids are analgesia and use indetoxification from opioid dependence, the formulations will typicallybe for systemic absorption, although topical pain relief can be providedby opioids and they are additionally of value in cough suppression(especially codeine and hydrocodone), diarrhoea suppression, anxiety dueto shortness of breath (especially oxymorphone) and antidepression(especially buprenorphine). For these, appropriate administrationmethods, such as bioadhesive pain-relieving gels for topical pain, ornon-absorbed oral compositions for diarrhoea suppression may be used.

In a further aspect, the present invention also provides a method forthe preparation of a liquid crystalline opioid composition (especially adepot composition) comprising exposing a pre-formulation comprising alow viscosity mixture of:

a) at least one neutral diacyl lipid and/or a tocopherol;

b) at least one phospholipid;

c) at least one biocompatible (preferably oxygen containing), organicsolvent;

and at least one opioid bioactive agent dissolved or dispersed in thelow viscosity mixture, to an aqueous fluid (particularly in vivo and/orparticularly a body fluid as indicated herein). Preferably thepre-formulation administered is a pre-formulation of the presentinvention as described herein. The exposure to a fluid “in vivo” mayevidently be internally within the body or a body cavity, or may be at abody surface such as a skin surface, depending upon the nature of thecomposition.

The liquid crystalline composition formed in this method is preferablybioadhesive as described herein.

In a still further aspect the present invention provides a process forthe formation of a pre-formulation suitable for the administration of anopioid bioactive agent to a (preferably mammalian) subject, said processcomprising forming a low viscosity mixture of

a) at least one neutral diacyl lipid and/or a tocopherol;

b) at least one phospholipid;

c) at least one biocompatible (preferably oxygen containing), organicsolvent; and dissolving or dispersing at least one opioid bioactiveagent in the low viscosity mixture, or in at least one of components a,b or c prior to forming the low viscosity mixture. Preferably thepre-formulation so-formed is a formulation of the invention as describedherein.

In a yet still further aspect the present invention provides the use ofa low viscosity mixture of:

a) at least one neutral diacyl lipid and/or a tocopherol;

b) at least one phospholipid;

c) at least one biocompatible (preferably oxygen containing), organicsolvent;

wherein at least one opioid bioactive agent is dissolved or dispersed inthe low viscosity mixture in the manufacture of a pre-formulation foruse in the sustained administration of said opioid active agent, whereinsaid pre-formulation is capable of forming at least one liquidcrystalline phase structure upon contact with an aqueous fluid.

In a still further aspect, the present invention additionally providesfor a method of treatment or prophylaxis of a human or non-human animalsubject comprising administration of a preformulation as describedherein. The invention additionally provides for the use of apreformulation as described herein in the manufacture of a medicamentfor use in treatment or prophylaxis as described herein.

As used herein, the term “low viscosity mixture” is used to indicate amixture which may be readily administered to a subject and in particularreadily administered by means of a standard syringe and needlearrangement. This may be indicated, for example by the ability to bedispensed from a 1 ml disposable syringe through a 22 awg (or a 23gauge) needle by manual pressure. In a particularly preferredembodiment, the low viscosity mixture should be a mixture capable ofpassing through a standard sterile filtration membrane such as a 0.22 μmsyringe filter. In other preferred embodiments, a similar functionaldefinition of a suitable viscosity can be defined as the viscosity of apre-formulation that can be sprayed using a compression pump orpressurized spray device using conventional spray equipment. A typicalrange of suitable viscosities would be, for example, 0.1 to 5000 mPas,preferably 1 to 1000 mPas at 20° C. (e.g. 10 to 1000 mPas or 50 to 1000mPas at 20° C.).

It has been observed that by the addition of small amounts of lowviscosity solvent, as indicated herein, a very significant change inviscosity can be provided. As indicated in Example 17 below, forexample, the addition of only 5% solvent (in the case of Example 17,ethanol) can reduce viscosity by several orders of magnitude addition of10% solvent will cause a still greater effect. In order to achieve thisnon-linear, synergistic effect, in lowering viscosity it is importantthat a solvent of appropriately low viscosity and suitable polarity beemployed. Such solvents include those described herein infra.

Particularly preferred examples of low viscosity mixtures are molecularsolutions and/or isotropic phases such as L₂ and/or L₃ phases. Asdescribe above, the L₃ is a non-lamellar phase of interconnected sheetswhich has some phase structure but lacks the long-range order of aliquid crystalline phase. Unlike liquid crystalline phases, which aregenerally highly viscous, L₃ phases are of lower viscosity. Obviously,mixtures of L₃ phase and molecular solution and/or particles of L₃ phasesuspended in a bulk molecular solution of one or more components arealso suitable. The L₂ phase is the so-called “reversed micellar” phaseor microemulsion. Most preferred low viscosity mixtures are molecularsolutions, L₃ phases and mixtures thereof. L₂ phases are less preferred,except in the case of swollen L₂ phases as described below.

The present invention provides a pre-formulation comprising componentsa, b, c and at least one opioid bioactive agent as indicated herein. Oneof the considerable advantages of the pre-formulations of the inventionis that components a and b may be formulated in a wide range ofproportions. In particular, it is possible to prepare and usepre-formulations of the present invention having a much greaterproportion of phospholipid to neutral, diacyl lipid and/or tocopherolthan was previously achievable without risking phase separation and/orunacceptably high viscosities in the pre-formulation. The weight ratiosof components a:b may thus be anything from 5:95 right up to 95:5.Preferred ratios would generally be from 90:10 to 20:80 and morepreferably from 85:15 to 30:70. A highly suitable range is a:b in theratio 40:60 to 80:20, especially around 50:50, e.g. 45:55 to 60:40. Inone preferred embodiment of the invention, there is a greater proportionof component b than component a. That is, the weight ratio a:b is below50:50, e.g. 48:52 to 2:98, preferably, 40:60 to 10:90 and morepreferably 35:65 to 20:80.

The amount of component c in the pre-formulations of the invention willbe at least sufficient to provide a low viscosity mixture (e.g. amolecular solution, see above) of components a, b and c and will beeasily determined for any particular combination of components bystandard methods. The phase behaviour itself may be analysed bytechniques such as visual observation in combination with polarizedlight microscopy, nuclear magnetic resonance, x-ray or neutrondiffraction, and cryo-transmission electron microscopy (cryo-TEM) tolook for solutions, L₂ or L₃ phases, or liquid crystalline phases.Viscosity may be measured directly by standard means. As describedabove, an appropriate practical viscosity is that which can effectivelybe syringed and particularly sterile filtered. This will be assessedeasily as indicated herein. The maximum amount of component c to beincluded will depend upon the exact application of the pre-formulationbut generally the desired properties will be provided by any amountforming a low viscosity mixture (e.g. a molecular solution, see above)and/or a solution with sufficiently low viscosity. Since theadministration of unnecessarily large amounts of solvent to a subject isgenerally undesirable the amount of component c will typically belimited to no more than ten times (e.g. three times) the minimum amountrequired to form a low viscosity mixture, preferably no more than fivetimes and most preferably no more than twice this amount. Thecomposition of the present invention may, however, contain a greaterquantity of solvent than would be acceptable in an immediate dosagecomposition. This is because the process by which the active agents areslowly released (e.g. formation of shells of liquid crystalline phase sedescribed herein) also serve to retard the passage of solvent from thecomposition. As a result, the solvent is released over some time (e.g.minutes or hours) rather than instantaneously and so can be bettertolerated by the body.

Higher proportions of solvent may also be used for non-parenteral (e.g.topical) applications, especially to body surfaces, where the solventwill be lost by evaporation rather than absorbed into the body. For suchapplications up to 100 times the minimum amount of solvent may be used(e.g. up to 95% by weight of the composition, preferably up to 80% byweight and more preferably up to 50% by weight), especially where a verythin layer of the resulting non-parenteral depot is desired.

Where the compositions of the invention are formulated as(non-parenteral) aerosol spray compositions (e.g. for topical orsystemic delivery of an active), the composition may also comprise apropellant. Such compositions may also include a high proportion ofsolvent component c), as considered above, since much of the solventwill evaporate when the composition is dispensed.

Suitable propellants are volatile compounds which will mix with thecomposition of the invention under the pressure of the spray dispenser,without generating high viscosity mixtures. They should evidently haveacceptable biocompatibility. Suitable propellants will readily beidentified by simple testing and examples include hydrocarbons(especially C₁ to C₄ hydrocarbons), carbon dioxide and nitrogen.Volatile hydrofluorocarbons such as HFCs 134, 134a, 227ea and/or 152amay also be suitable.

As a general guide, the weight of component c will typically be around0.5 to 50% of the total weight of the a-b-c solution. This proportion ispreferably (especially for injectable depots) 2 to 30% and morepreferably 5 to 20% by weight. A highly suitable range is around 5%,e.g. 1 to 10%, especially, 3 to 8% by weight of the completecomposition.

Component “a” as indicated herein is a neutral lipid componentcomprising a polar “head” group and also non-polar “tail” groups.Generally the head and tail portions of the lipid will be joined by anester moiety but this attachment may be by means of an ether, an amide,a carbon-carbon bond or other attachment. Preferred polar head groupsare non-ionic and include polyols such as glycerol, diglycerol and sugarmoieties (such as inositol and glucosyl based moieties); and esters ofpolyols, such as acetate or succinate esters. Preferred polar groups areglycerol and diglycerol, especially glycerol.

In one preferred aspect, component a is a diacyl lipid in that it hastwo non-polar “tail” groups. This is generally preferable to the use ofmono-acyl (“lyso”) lipids because these are typically less welltolerated in vivo. The two non-polar groups may have the same or adiffering number of carbon atoms and may each independently be saturatedor unsaturated. Examples of non-polar groups include C₆-C₃₂ alkyl andalkenyl groups, which are typically present as the esters of long chaincarboxylic acids. These are often described by reference to the numberof carbon atoms and the number of unsaturations in the carbon chain.Thus, CX:Z indicates a hydrocarbon chain having X carbon atoms and Zunsaturations. Examples particularly include caproyl (C6:0), capryloyl(C8:0), capryl (C10:0), lauroyl (C12:0), myristoyl (C14:0), palmitoyl(C16:0), phytanoly (C16:0), palmitoleoyl (C16:1), stearoyl (C18:0),oleoyl (C18:1), elaidoyl (C18:1), linoleoyl (C18:2), linolenoyl (C18:3),arachidonoyl (C20:4), behenoyl (C22:0) and lignoceroyl (C24:9) groups.Thus, typical non-polar chains are based on the fatty acids of naturalester lipids, including caproic, caprylic, capric, lauric, myristic,palmitic, phytanic, palmitolic, stearic, oleic, elaidic, linoleic,linolenic, arachidonic, behenic or lignoceric acids, or thecorresponding alcohols. Preferable non-polar chains are palmitic,stearic, oleic and linoleic acids, particularly oleic acid.

The diacyl lipid, when used as all or part of component “a”, may besynthetic or may be derived from a purified and/or chemically modifiednatural sources such as vegetable oils. Mixtures of any number of diacyllipids may be used as component a. Most preferably this component willinclude at least a portion of diacyl glycerol (DAG), especially glyceroldioleate (GDO). In one favoured embodiment, component a consists ofDAGs. These may be a single DAG or a mixture of DAGs. A highly preferredexample is DAG comprising at least 50%, preferably at least 80% and evencomprising substantially 100% GDO.

An alternative or additional highly preferred class of compounds for useas all or part of component a are tocopherols. As used herein, the term“a tocopherol” is used to indicate the non-ionic lipid tocopherol, oftenknown as vitamin E, and/or any suitable salts and/or analogues thereof.Suitable analogues will be those providing the phase-behaviour, lack oftoxicity, and phase change upon exposure to aqueous fluids, whichcharacterise the compositions of the present invention. Such analogueswill generally not form liquid crystalline phase structures as a purecompound in water. The most preferred of the tocopherols is tocopherolitself, having the structure below. Evidently, particularly where thisis purified from a natural source, there may be a small proportion ofnon-tocopherol “contaminant” but this will not be sufficient to alterthe advantageous phase-behaviour or lack of toxicity. Typically, atocopherol will contain no more than 10% of non-tocopherol-analoguecompounds, preferably no more than 5% and most preferably no more than2% by weight.

In one embodiment of the invention, component a) consists essentially oftocopherols, in particular tocopherol as shown above.

A preferred combination of constituents for component a) is a mixture ofat least one DAG (e.g. GDO) with at least one tocopherol. Such mixturesinclude 2:98 to 98:2 by weight tocopherol:GDO, e.g. 10:90 to 90:10tocopherol:GDO and especially 20:80 to 80:20 of these compounds. Similarmixtures of tocopherol with other DAGs are also suitable. Component a)may be present in an amount of between 18% by weight and 72% by weight.

Component “b” in the present invention is at least one phospholipid. Aswith component a, this component comprises a polar head group and atleast one non-polar tail group. The difference between components a andb lies principally in the polar group. The non-polar portions may thussuitably be derived from the fatty acids or corresponding alcoholsconsidered above for component a. It will typically be the case that thephospholipid will contain two non-polar groups, although one or moreconstituents of this component may have one non-polar moiety. Where morethan one non-polar group is present these may be the same or different.

Preferred phospholipid polar “head” groups include phosphatidylcholine,phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol.Most preferred is phosphatidylcholine (PC). In a preferred embodiment,component b) thus consists of at least 50% PC, preferably at least 70%PC and most preferably at least 80% PC. Component b) may consistessentially of PC.

The phospholipid portion, even more suitably than any diacyl lipidportion, may be derived from a natural source. Suitable sources ofphospholipids include egg, heart (e.g. bovine), brain, liver (e.g.bovine) and plant sources including soybean. Such sources may provideone or more constituents of component b, which may comprise any mixtureof phospholipids.

Since the pre-formulations of the invention are to be administered to asubject for the controlled release of an active agent, it is preferablethat the components a and b are biocompatible. In this regard, it ispreferable to use, for example, diacyl lipids and phospholipids ratherthan mono-acyl(lyso) compounds. A notable exception to this istocopherol, as described above. Although having only one alkyl chain,this is not a “lyso” lipid in the convention sense. The nature oftocopherol as a well tolerated essential vitamin evidently makes ithighly suitable in biocompatibility.

It is furthermore most preferable that the lipids and phospholipids ofcomponents a and b are naturally occurring (whether they are derivedfrom a natural source or are of synthetic origin). Naturally occurringlipids tend to cause lesser amounts of inflammation and reaction fromthe body of the subject. Not only is this more comfortable for thesubject but it may increase the residence time of the resulting depotcomposition, especially for parenteral depots, since less immune systemactivity is recruited to the administration site. In certain cases itmay, however, be desirable to include a portion of anon-naturally-occurring lipid in components a and/or b. This might be,for example an “ether lipid” in which the head and tail groups arejoined by an ether bond rather than an ester. Suchnon-naturally-occurring lipids may be used, for example, to alter therate of degradation of the resulting depot-composition by having agreater or lesser solubility or vulnerability to breakdown mechanismspresent at the site of active agent release. Although all proportionsfall within the scope of the present invention, generally, at least 50%of each of components a and b will be naturally occurring lipids. Thiswill preferably be at least 75% and may be up to substantially 100%.

Two particularly preferred combinations of components a and b are GDOwith PC and tocopherol with PC, especially in the region 30-90 wt %GDO/tocopherol, 10-60 wt % PC and 1-30% solvent (especially ethanol, NMPand/or ispropanol). A composition of 40-80% GDO, 20-60% PC, with 3-20%,preferably 5-10% solvent (e.g. ethanol, benzylalcohol, propyleneglycol,benzyl benzoate, dimethylsulphoxide etc) and 1-15%, preferably 5-10% ofat least one opioid active agent is particularly effective. A ratio ofPC/GDO: ˜0.25-1.5, preferably 0.8-1.2 is desirable in many cases.

In addition to amphiphilic components a and b, the pre-formulations ofthe invention may also contain additional amphiphilic components atrelatively low levels. In one embodiment of the invention, thepre-formulation contains up to 10% (by weight of components a and b) ofa charged amphiphile, particularly an anionic amphiphile such as a fattyacid. Preferred fatty acids for this purpose include caproic, caprylic,capric, lauric, myristic, palmitic, phytanic, palmitolic, stearic,oleic, elaidic, linoleic, linolenic, arachidonic, behenic or lignocericacids, or the corresponding alcohols. Preferable fatty acids arepalmitic, stearic, oleic and linoleic acids, particularly oleic acid. Itis particularly advantageous that this component be used in combinationwith a cationic peptide active agent (see below). The combination of ananionic lipid and a cationic peptide is believed to provide a sustainedrelease composition of particular value. This may in part be due toincreased protection of the peptide from the degradative enzymes presentin vivo.

Component “c” of the pre-formulations of the invention is an oxygencontaining organic solvent. Since the pre-formulation is to generate adepot composition following administration (e.g. in vivo), upon contactwith an aqueous fluid, it is desirable that this solvent be tolerable tothe subject and be capable of mixing with the aqueous fluid, and/ordiffusing or dissolving out of the pre-formulation into the aqueousfluid. Solvents having at least moderate water solubility are thuspreferred.

In a preferred version, the solvent is such that a relatively smalladdition to the composition comprising a and b, i.e. below 20% (e.g.3-20%), or more preferably below 10% (e.g. 5 to 10%), give a largeviscosity reductions of one order of magnitude or more. As describedherein, the addition of 5% or 10% solvent can give a reduction ofseveral orders of magnitude in viscosity over the solvent-freecomposition, even if that composition is a solution or L₂ phasecontaining no solvent, or an unsuitable solvent such as water (subjectto the special case considered below), or glycerol. See Example 17 belowfor example.

Typical solvents suitable for use as component c include at least onesolvent selected from alcohols, ketones, esters (including lactones),ethers, amides and sulphoxides. Examples of suitable alcohols includeethanol, isopropanol, benzylalcohol and glycerol formal. Monools arepreferred to diols and polyols. Where diols or polyols are used, this ispreferably in combination with an at least equal amount of monool orother preferred solvent. Examples of ketones include acetone andpropylene carbonate. Suitable ethers include diethylether, glycofurol,diethylene glycol monoethyl ether, dimethylisobarbide, and polyethyleneglycols. Suitable esters include ethyl acetate, benzyl benzoate andisopropyl acetate and dimethyl sulphide is as suitable sulphide solvent.Suitable amides and sulphoxides include dimethylacetamide (DMA),n-methylpyrrolidone (NMP), 2-pyrrolidone and dimethylsulphoxide (DMSO).Less preferred solvents include dimethyl isosorbide, tetrahydrofurfurylalcohol, diglyme and ethyl lactate.

Since the pre-formulations are to be administered to a living subject,it is necessary that the solvent component c is sufficientlybiocompatible. The degree of this biocompatibility will depend upon theapplication method and since component c may be any mixture of solvents,a certain amount of a solvent that would not be acceptable in largequantities may evidently be present. Overall, however, the solvent ormixture forming component c must not provoke unacceptable reactions fromthe subject upon administration. Generally such solvents will behydrocarbons or preferably oxygen containing hydrocarbons, bothoptionally with other substituents such as nitrogen containing groups.It is preferable that little or none of component c contains halogensubstituted hydrocarbons since these tend to have lowerbiocompatibility. Where a portion of halogenated solvent such asdichloromethane or chloroform is necessary, this proportion willgenerally be minimised. Where the depot composition is to be formednon-parenterally a greater range of solvents may evidently be used thanwhere the depot is to be parenteral.

Component c as used herein may be a single solvent or a mixture ofsuitable solvents but will generally be of low viscosity. This isimportant because one of the key aspects of the present invention isthat it provides preformulations that are of low viscosity and a primaryrole of a suitable solvent is to reduce this viscosity. This reductionwill be a combination of the effect of the lower viscosity of thesolvent and the effect of the molecular interactions between solvent andlipid composition. One observation of the present inventors is that theoxygen-containing solvents of low viscosity described herein have highlyadvantageous and unexpected molecular interactions with the lipid partsof the composition, thereby providing a non-linear reduction inviscosity with the addition of a small volume of solvent.

The viscosity of the “low viscosity” solvent component c (single solventor mixture) should typically be no more than 18 mPas at 20° C. This ispreferably no more than 15 mPas, more preferably no more than 10 mPasand most preferably no more than 7 mPas at 20° C.

The solvent component c will generally be at least partially lost uponin vivo formation of the depot composition, or diluted by absorption ofwater from the surrounding air and/or tissue. It is preferable,therefore, that component c be at least to some extent water miscibleand/or dispersible and at least should not repel water to the extentthat water absorption is prevented. In this respect also, oxygencontaining solvents with relatively small numbers of carbon atoms (forexample up to 10 carbons, preferably up to 8 carbons) are preferred.Obviously, where more oxygens are present a solvent will tend to remainsoluble in water with a larger number of carbon atoms. The carbon toheteroatom (e.g. N, O, preferably oxygen) ratio will thus often bearound 1:1 to 6:1, preferably 2:1 to 4:1. Where a solvent with a ratiooutside one of these preferred ranges is used then this will preferablybe no more than 75%, preferably no more than 50%, in combination with apreferred solvent (such as ethanol). This may be used, for example todecrease the rate of evaporation of the solvent from the pre-formulationin order to control the rate of liquid crystalline depot formation.

A further advantage of the present pre-formulations is that a higherlevel of bioactive agent may be incorporated into the system. Inparticular, by appropriate choice of components a-c (especially c), highlevels of active agent may be dissolved or suspended in thepre-formulations. Generally, the lipid components in the absence ofwater are relatively poorly solubilising but in the presence of waterform phases too viscous to administer easily. Higher proportions ofbioactive agent may be included by use of appropriate solvents ascomponent c and this level will either dissolve in the depot compositionas it forms in situ or may form microdrops or microcrystals which willgradually dissolve and release active agent. A suitable choice ofsolvent will be possible by routine experimentation within theguidelines presented herein.

The pre-formulations of the present invention typically do not containsignificant amounts of water. Since it is essentially impossible toremove every trace of water from a lipid composition, this is to betaken as indicating that only such minimal trace of water exists ascannot readily be removed. Such an amount will generally be less than 1%by weight, preferably less that 0.5% by the weight of thepre-formulation. In one preferred aspect, the pre-formulations of theinvention do not contain glycerol, ethylene glycol or propylene glycoland contain no more than a trace of water, as just described.

There is, however, a certain embodiment of the present invention inwhich higher proportions of water may be tolerated. This is where wateris present as a part of the solvent component in combination with anadditional water-miscible component c (single solvent or mixture). Inthis embodiment, up to 10 wt % water may be present providing that atleast 3 wt %, preferably at least 5% and more preferably at least 7 wt %component c is also present, that component c is water miscible, andthat the resulting preformulation remains non-viscous and thus does notform a liquid crystalline phase. Generally there will be a greateramount of component c) by weight than the weight of water included inthe preformulation. Most suitable solvents of use with water in thisaspect of the invention include ethanol, isopropyl alcohol, NMP, acetoneand ethyl acetate.

The pre-formulations of the present invention contain one or more opioidbioactive agents (described equivalently as “bioactive agents” or simply“active agents” herein). Active agents may be any opioid compound havingan effect (e.g. agonism and/or antagonism) at one or more opioidreceptors. Structurally, these may be peptides, such as the endogenousopioids (e.g. endorphins, dynorphins, enkephalins, and derivativesthereof), may be one of the natural opium alkaloids (the opiatesmorphine, codeine or thebaine), any of the numerous semi-syntheticopioids (typically derivatives of opiates such as diacetylmorphine(heroin), oxycodone, hydrocodone, dihydrocodeine, hydromorphone,oxymorphone, nicomorphine), or any of the wide range of fully syntheticopioids including anilidopiperidines (e.g. fentanyl, sufentanil),phenylpiperidines (e.g. pethidine (meperidine), ketobemidone, MPPP),diphenylpropylamine derivatives (e.g. bezitramide, methadone,levo-alphacetylmethadol (LAAM), loperamide, diphenoxylate),benzomorphane derivatives (e.g. pentazocine, phenazocine), oripavinederivatives (e.g. buprenorphine, etorphine), morphinan derivatives (e.g.butorphanol, levorphanol, levomethorphan, plus opioid antagonists suchas naloxone and naltrexone and atypical opioids such as tramadol. Theactive agents will be formulated at a level sufficient to provide an invivo concentration at a functional level (including local concentrationsfor topical compositions).

The opioid drugs which may be delivered by the composition of thepresent are analgesics, and some have shown utility as antidepressants,and in treatment of diarrhoea.

In the present case, the most preferred opioids are those with arelatively long half-life (e.g. greater than 18 hours) in humans, suchthat they may be used for long-term depot compositions in detoxificationor maintenance in opioid dependents and addicts. Diphenylpropylaminederivatives such as methadone and oripavine derivatives such asbuprenorphine are preferred, with buprenorphine being the most preferredactive agent.

Buprenorphine is an opioid with mixed agonist-antagonist properties thathas been used in the treatment of opioid dependence in a number ofcountries. It is approved by the Food and Drug Administration (FDA) forthe treatment of opioid dependence in the United States and clinicalstudies have shown buprenorphine to be effective in reducingopioid-positive urines and retaining patients in outpatient maintenancetreatment of opioid dependence, as well as in the detoxification ofopioid abusers.

Buprenorphine has a unique pharmacological profile with severalpotential strengths over other opioid treatments:

1. A ceiling on its agonist activity that may reduce its abuse liabilityand contribute to a superior safety profile.

2. Attenuation of physiological and subjective effects which likelycontributes to the suppression of opioid self-administration.

3. Slow receptor dissociation providing extended duration.

Importantly, buprenorphine treatment is associated with a relativelylow-intensity withdrawal syndrome upon discontinuation, making itparticularly promising for detoxification treatments.

Buprenorphine is currently available in sublingual dosing forms, whichrequire dosing every 1-2 days either at a clinic, or with “take-home”medication. Because of the potential for abuse of opioids, however,“take-home” of any opioid poses potential logistic and legislativeproblems.

A depot formulation of the present invention offers several advantagesin use for treating opioid dependence, including fast onset andrelatively stable levels of buprenorphine over time, thereby suppressingwithdrawal symptoms and blocking the effects of exogenously-administeredopioids for several weeks. The slow decay and elimination of the depotbuprenorphine could also provide a gradual opioid detoxification withminimal withdrawal syndrome. Hence, a buprenorphine depot may offer apromising approach for delivering effective opioid maintenance ordetoxification treatment. Furthermore, a depot formulation of shouldminimize the burdens of patient compliance as it would require a lessfrequent dosing regimen, thereby also reducing the frequency of clinicvisits and the amount of clinical support needed. Finally, depotbuprenorphine should reduce the risks of misuse and drug diversion ofthe medication by eliminating or reducing the need for take-homemedication.

The amount of bioactive agent to be formulated with the pre-formulationsof the present invention will depend upon the functional dose and theperiod during which the depot composition formed upon administration isto provide sustained release. Typically, the dose formulated for aparticular agent will be around the equivalent of the normal daily dosemultiplied by the number of days the formulation is to provide release.Evidently this amount will need to be tailored to take into account anyadverse effects of a large dose at the beginning of treatment and sothis will generally be the maximum dose used. The precise amountsuitable in any case will readily be determined by suitableexperimentation.

In one embodiment, the pre-formulations of the present invention willgenerally be administered parenterally. This administration willgenerally not be an intra-vascular method but will preferably besubcutaneous intracavitary or intramuscular. Typically theadministration will be by injection, which term is used herein toindicate any method in which the formulation is passed through the skin,such as by needle, catheter or needle-less injector.

In parenteral (especially subcutaneous) depot precursors, preferredactive agents are those suitable for systemic administration includingtramadol, fentanyl, morphine, hydromorphone, methadone, oxycodone,codeine, and buprenorphine.

In an alternative embodiment, the formulations of the present inventionmay form non-parenteral depots where the active agent is slowly releasedat a body surface. It is especially important in this embodiment thatthe pre-formulations of the invention and/or the liquid crystallinedepot compositions formed therefrom should preferably be bioadhesive.That is to say that the compositions should coat the surface to whichthey are applied and/or upon which they form as appropriate and shouldremain even when this surface is subject to a flow of air or liquidand/or rubbing. It is particularly preferable that the liquidcrystalline depot compositions formed should be stable to rinsing withwater. For example, a small volume of depot precursor may be applied toa body surface and be exposed to a flow of five hundred times its ownvolume of water per minute for 5 minutes. After this treatment, thecomposition can be considered bioadhesive if less than 50% of thebioactive agent has been lost. Preferably this level of loss will bematched when water equaling 1000 times and more preferably 10 000 timesthe volume of the composition is flowed past per minute for five, orpreferably 10, minutes.

Although the non-parenteral depot compositions of the present inventionmay absorb some or all of the water needed to form a liquid crystallinephase structure from the biological surfaces with which they arecontacted, some additional water may also be absorbed from thesurrounding air. In particular, where a thin layer of high surface areais formed then the affinity of the composition for water may besufficient for it to form a liquid crystalline phase structure bycontact with the water in the air. The “aqueous fluid” referred toherein is thus, at least partially, air containing some moisture in thisembodiment.

Non-parenteral depot compositions will typically be generated byapplying the pre-formulation topically to a body surface or to a naturalor artificially generated body cavity and/or to the surface of animplant. This application may be by direct application of liquid such asby spraying, dipping, rinsing, application from a pad or ball roller,intra-cavity injection (e.g. to an open cavity with or without the useof a needle), painting, dropping (especially into the eyes) and similarmethods. A highly effective method is aerosol or pump spraying andevidently this requires that the viscosity of the pre-formulation be aslow as possible and is thus highly suited to the compositions of theinvention. Non-parenteral depots may, however, be used to administersystemic opioid agents e.g. transmucosally or transdermally.

Most opioids are suitable for non-parenteral administration, includingtramadol, fentanyl, morphine, hydromorphone, methadone, oxycodone,codeine, and buprenorphine.

Some other specific opioid actives found by the inventors to form highlyeffective depots of the present invention include the following:

For topical bioadhesive, controlled release products for intraoral(including buccal & periodontal) administration;

-   i. tramadol (analgesic). Provides a composition with sustained    systemic analgesic effect.

Depot is formable having high level of active agent incorporation andhigh degree of resistance to washing away. Preformulations are in theform of a liquid administered as spray or liquid wash/rinse.

For non-parenteral (e.g. topical or systemic) bioadhesive, controlledrelease products for nasal administration;

-   ii. fentanyl (analgesic). Provides rapid onset and sustained    duration analgesia when administered as spray

The pre-formulations of the present invention provide non-lamellarliquid crystalline depot compositions upon exposure to aqueous fluids,especially in vivo and in contact with body surfaces. As used herein,the term “non-lamellar” is used to indicate a normal or reversed liquidcrystalline phase (such as a cubic or hexagonal phase) or the L₃ phaseor any combination thereof. The term liquid crystalline indicates allhexagonal, all cubic liquid crystalline phases and/or all mixturesthereof. Hexagonal as used herein indicates “normal” or “reversed”hexagonal (preferably reversed) and “cubic” indicates any cubic liquidcrystalline phase unless specified otherwise. By use of thepre-formulations of the present invention it is possible to generate anyphase structure present in the phase-diagram of components a and b withwater. This is because the pre-formulations can be generated with awider range of relative component concentrations than previous lipiddepot systems without risking phase separation or resulting in highlyviscous solutions for injection. In particular, the present inventionprovides for the use of phospholipid concentrations above 50% relativeto the total amphiphile content. This allows access to phases only seenat high phospholipid concentrations, particularly the hexagonal liquidcrystalline phases.

For many combinations of lipids, only certain non-lamellar phases exist,or exist in any stable state. It is a surprising feature of the presentinvention that compositions as described herein frequently exhibitnon-lamellar phases which are not present with many other combinationsof components. In one particularly advantageous embodiment, therefore,the present invention relates to compositions having a combination ofcomponents for which an I₂ and/or L₂ phase region exists when dilutedwith aqueous solvent. The presence or absence of such regions can betested easily for any particular combination by simple dilution of thecomposition with aqueous solvent and study of the resulting phasestructures by the methods described herein.

In a highly advantageous embodiment, the compositions of the inventionmay form an I₂ phase, or a mixed phase including I₂ phase upon contactwith water. The I₂ phase is a reversed cubic liquid crystalline phasehaving discontinuous aqueous regions. This phase is of particularadvantage in the controlled release of active agents and especially incombination with polar active agents, such as water soluble activesbecause the discontinuous polar domains prevent rapid diffusion of theactives. Depot precursors in the L₂ are highly effective in combinationwith an I₂ phase depot formation. This is because the L₂ phase is aso-called “reversed micellar” phase having a continuous hydrophobicregion surrounding discrete polar cores. L₂ thus has similar advantageswith hydrophilic actives.

In transient stages after contact with body fluid the composition cancomprise multiple phases since the formation of an initial surface phasewill retard the passage of solvent into the core of the depot,especially with substantial sized administrations of internal depots.Without being bound by theory, it is believed that this transientformation of a surface phase, especially a liquid crystalline surfacephase, serves to dramatically reduce the “burst/lag” profile of thepresent compositions by immediately restricting the rate of exchangebetween the composition and the surroundings. Transient phases mayinclude (generally in order from the outside towards the centre of thedepot): H_(II) or L_(α), I₂, L₂, and liquid (solution). It is highlypreferred that the composition of the invention is capable forming atleast two and more preferably at least three of these phasessimultaneously at transient stages after contact with water atphysiological temperatures. In particular, it is highly preferred thatone of the phases formed, at least transiently, is the I₂ phase.

It is important to appreciate that the preformulations of the presentinvention are of low viscosity. As a result, these preformulations mustnot be in any bulk liquid crystalline phase since all liquid crystallinephases have a viscosity significantly higher than could be administeredby syringe or spray dispenser. The preformulations of the presentinvention will thus be in a non-liquid crystalline state, such as asolution, L₂ or L₃ phase, particularly solution or L₂. The L₂ phase asused herein throughout is preferably a “swollen” L₂ phase containinggreater than 10 wt % of solvent (component c) having a viscosityreducing effect. This is in contrast to a “concentrated” or “unswollen”L₂ phase containing no solvent, or a lesser amount of solvent, orcontaining a solvent (or mixture) which does not provide the decrease inviscosity associated with the oxygen-containing, low viscosity solventsspecified herein.

Upon administration, the pre-formulations of the present inventionundergo a phase structure transition from a low viscosity mixture to ahigh viscosity (generally tissue adherent) depot composition. Generallythis will be a transition from a molecular mixture, swollen L₂ and/or L₃phase to one or more (high viscosity) liquid crystalline phases such asnormal or reversed hexagonal or cubic liquid crystalline phases ormixtures thereof. As indicated above, further phase transitions may alsotake place following administration. Obviously, complete phasetransition is not necessary for the functioning of the invention but atleast a surface layer of the administered mixture will form a liquidcrystalline structure. Generally this transition will be rapid for atleast the surface region of the administered formulation (that part indirect contact with air, body surfaces and/or body fluids). This willmost preferably be over a few seconds or minutes (e.g. up to 30 minutes,preferably up to 10 minutes, more preferably 5 minutes of less). Theremainder of the composition may change phase to a liquid crystallinephase more slowly by diffusion and/or as the surface region disperses.

In one preferred embodiment, the present invention thus provides apre-formulation as described herein of which at least a portion forms ahexagonal liquid crystalline phase upon contact with an aqueous fluid.The thus-formed hexagonal phase may gradually disperse, releasing theactive agent, or may subsequently convert to a cubic liquid crystallinephase, which in turn then gradually disperses. It is believed that thehexagonal phase will provide a more rapid release of active agent, inparticular of hydrophilic active agent, than the cubic phase structure,especially the I₂ and L₂ phase. Thus, where the hexagonal phase formsprior to the cubic phase, this will result in an initial release ofactive agent to bring the concentration up to an effective levelrapidly, followed by the gradual release of a “maintenance dose” as thecubic phase degrades. In this way, the release profile may becontrolled.

Without being bound by theory, it is believed that upon exposure (e.g.to body fluids), the pre-formulations of the invention lose some or allof the organic solvent included therein (e.g. by diffusion and/orevaporation) and take in aqueous fluid from the bodily environment (e.g.moist air close to the body or the in vivo environment) such that atleast a part of the formulation generates a non-lamellar, particularlyliquid crystalline phase structure. In most cases these non-lamellarstructures are highly viscous and are not easily dissolved or dispersedinto the in vivo environment and are bioadhesive and thus not easilyrinsed or washed away. Furthermore, because the non-lamellar structurehas large polar, apolar and boundary regions, it is highly effective insolubilising and stabilising many types of active agents and protectingthese from degradation mechanisms. As the depot composition formed fromthe pre-formulation gradually degrades over a period of days, weeks ormonths, the active agent is gradually released and/or diffuses out fromthe composition. Since the environment within the depot composition isrelatively protected, the pre-formulations of the invention are highlysuitable for active agents with a relatively low biological half-life(see above).

It is an unexpected finding of the present inventors that thepre-formulations result in a depot composition that have very little“burst” effect in the active agent release profile. This is unexpectedbecause it might be expected that the low viscosity mixture (especiallyif this is a solution) of the pre-composition would rapidly lose activeagent upon exposure to water. In fact, pre-formulations of the inventionhave shown considerably less of an initial “burst” than previously knownpolymer-base depot compositions. This is illustrated in the Examplesbelow and Figures attached hereto. In one embodiment, the invention thusprovides injectable preformulations and resulting depot compositionswherein the highest plasma concentration of active after administrationis no more than 5 times the average concentration between 24 hours and 5days of administration. This ratio is preferably no more than 4 timesand most preferably no more than 3 times the average concentration.

In an additional aspect of the invention, the topical compositions maybe used to provide a physical barrier on body surfaces, in the absenceof any active agent. In particular, because of the very highbioadherance of the compositions, “barrier” coatings formed by sprayingor application of liquid may be formed from the present compositions soas to reduce contact with potential infective or irritant agents or toreduce soiling of the body surfaces. The robust nature of thecompositions and resistance to washing provide advantageouscharacteristics for such barriers, which could conveniently be appliedas a liquid or by spraying.

The methods of treatment and/or prophylaxis, and corresponding uses inmanufacture, of the present invention will be for any medical indicationfor which opioids are indicated. In particular, chronic conditions suchas chronic pain (e.g. in arthritis, after surgery, in palliative cancertreatment etc.) are particularly suitable for the use of the presentdepot formulations and their precursors. The most suitable indicationswill, however, include pain, diarrhoea, depression, opioid dependence,opioid addiction, and the symptoms of opioid withdrawal. Of these, thepresent compositions, especially when formulated with buprenorphine aremost preferably used in methods for the treatment and/or prophylaxis ofopioid dependence, opioid addiction, and/or the symptoms of opioidwithdrawal. Cases where opioid dependence and/or opioid addiction haveresulted from opioid abuse are particularly suitable for treatment withthe present compositions because they offer advantages in terms ofpatient compliance, where the patient's lifestyle may not be compatiblewith regular attendance at a clinic or other site of medical treatment.

The Invention will now be further illustrated by reference to thefollowing non-limiting Examples and the attached Figures, in which;

FIG. 1 shows the cumulative release of methylene blue (MB) from a depotformulation comprising PC/GDO/EtOH (45/45/10 wt %) when injected intoexcess water;

FIG. 2 demonstrates the non-linear decrease of pre-formulation viscosityupon addition of N-methylpyrrolidinone (NMP) and ethanol (EtOH);

FIG. 3 Shows the pharmacokinetic profile following administration ofdifferent dose volumes of buprenorphine (Example 19) to rats.

EXAMPLES Example 1 Availability of Various Liquid Crystalline Phases inthe Depot by Choice of Composition

Injectable formulations containing different proportions of phosphatidylcholine (“PC”—Epikuron 200) and glycerol dioleate (GDO) and with EtOH assolvent were prepared to illustrate that various liquid crystallinephases can be accessed after equilibrating the depot precursorformulation with excess water.

Appropriate amounts of PC and EtOH were weighed in glass vials and themixture was placed on a shaker until the PC completely dissolved to forma clear liquid solution. GDO was then added to form an injectablehomogenous solution.

Each formulation was injected in a vial and equilibrated with excesswater. The phase behaviour was evaluated visually and between crossedpolarizes at 25° C. Results are presented in Table 1.

TABLE 1 Formulation PC (wt %) GDO (wt %) EtOH (wt %) Phase in H₂O A 22.567.5 10.0 L₂ B 28.8 61.2 10.0 I₂ C 45.0 45.0 10.0 H_(II) D 63.0 27.010.0 H_(II)/L_(α) L₂ = reversed micellar phase I₂ = reversed cubicliquid crystalline phase H_(II) = reversed hexagonal liquid crystallinephase L_(α) = lamellar phase

Example 2 In Vitro Release of a Water-Soluble Substance

A water-soluble colorant, methylene blue (MB) was dispersed informulation C (see Example 1) to a concentration of 11 mg/g formulation.When 0.5 g of the formulation was injected in 100 ml water a stiffreversed hexagonal H_(II) phase was formed. The absorbency of MBreleased to the aqueous phase was followed at 664 nm over a period of 10days. The release study was performed in an Erlenmeyer flask at 37° C.and with low magnetic stirring.

The release profile of MB (see FIG. 1) from the hexagonal phaseindicates that this (and similar) formulations are promising depotsystems. Furthermore, the formulation seems to give a low initial burst,and the release profile indicates that the substance can be released forseveral weeks; only about 50% of MB is released after 10 days.

Example 3 Viscosity in PC/GDO (5:5) or PC/GDO (4:6) on Addition ofSolvent (EtOH, PG and NMP)

A mixture of PC/GDO/EtOH with approximately 25% EtOH was manufacturedaccording to the method in Example 1. All, or nearly all, of the EtOHwas removed from the mixture with a rotary evaporator (vacuum, 40° C.for 1 h followed by 50° C. for 2 h) and the resulting mixture wasweighed in glass vial after which 1, 3, 5, 10 or 20% of a solvent (EtOH,propylene glycol (PG) or n-methylpyrrolidone (NMP)) was added. Thesamples were allowed to equilibrate several days before the viscositywas measured with a CarriMed CSL 100 rheometer equipped with automaticgap setting.

This example clearly illustrates the need for solvent with certain depotprecursors in order to obtain an injectable formulation (see FIG. 2).The viscosity of solvent-free PC/GDO mixtures increases with increasingratio of PC. Systems with low PC/GDO ratio (more GDO) are injectablewith a lower concentration of solvent.

Example 4 Preparation of Depot Precursor Compositions with VariousSolvents

Depending on composition of the formulation and the nature andconcentration of active substance certain solvents may be preferable.

Depot precursor formulations (PC/GDO/solvent (36/54/10)) were preparedby with various solvents; NMP, PG, PEG400, glycerol/EtOH (90/10) by themethod of Example 1. All depot precursor compositions were homogeneousone phase solutions with a viscosity that enabled injection through asyringe (23 G—i.e. 23 gauge needle; 0.6 mm×30 mm). After injectingformulation precursors into excess water a liquid crystalline phase inthe form of a high viscous monolith rapidly formed with NMP and PGcontaining precursors. The liquid crystalline phase had a reversed cubicmicellar (I₂) structure. With PEG400, glycerol/EtOH (90/10) theviscosification/solidification process was much slower and initially theliquid precursor transformed to a soft somewhat sticky piece. Thedifference in appearance probably reflects the slower dissolution ofPEG400 and glycerol towards the excess aqueous phase as compared to thatof EtOH, NMP and PG.

Example 5 Robustness of the Behaviour of the Formulation AgainstVariations in the Excipient Quality

Depot precursor formulations were prepared with several different GDOqualities (supplied by Danisco, Dk), Table 3, using the method ofExample 1. The final depot precursors contained 36% wt PC, 54% wt GDO,and 10% wt EtOH. The appearance of the depot precursors was insensitiveto variation in the quality used, and after contact with excess water amonolith was formed with a reversed micellar cubic phase behaviour (I₂structure).

TABLE 3 Tested qualities of GDO. Triglyceride GDO quality Monoglyceride(% wt) Diglyceride (% wt) (% wt) A 10.9 87.5 1.6 B 4.8 93.6 1.6 C 1.097.3 1.7 D 10.1 80.8 10.1 E 2.9 88.9 8.2 F 0.9 89.0 10.1

Example 6 Preparation of Depot Composition Containing Saturated PC(Epikuron 200SH)

Depot precursor formulations were prepared with various amounts PCcomprising saturated hydrocarbon chains by addition of Epikuron 200SHdirectly to a mixture of PC/GDO/EtOH, prepared as for Example 1. Theformulations are shown in Table 4. All precursor formulations werehomogenous one phase samples in RT, while they became more viscous withincreasing amount Epikuron 200SH. Injecting the depot precursor intoexcess water gave a monolith comprising a reversed miceller cubic (I₂)structure. Monoliths formed from samples containing higher amounts ofEpikuron 200SH became turbid, possibly indicating segregation betweenEpikuron 200SH and the other components upon exposure to water andformation of the I₂ phase.

TABLE 4 Depot composition containing saturated PC Saturated PC, EpikuronPC GDO Formulation 200SH (% wt) (% wt) (% wt) EtOH (% wt) G1 3.9 34.651.9 9.6 G2 7.0 33.5 50.2 9.3 G3 14.3 30.8 46.3 8.6

Example 7 Degradation of Depot Formulation in the Rat

Various volumes (1, 2, 6 ml/kg) of the depot precursor (36% wt PC, 54%wt GDO, and 10% wt EtOH) were injected in the rat and were removed againafter a period of 14 days. It was found that substantial amounts of theformulations were still present subcutaneously in the rat after thistime, see Table 6.

TABLE 6 Mean diameter of depot monolith. Dose (ml/kg) Mean diameter day3 (mm) Mean diameter day 14 (mm) 1 (n = 3) 15.8 12.5 2 (n = 3) 18.5 15.36 (n = 3) 23.3 19.3

Example 8 In Vitro Study of Formation of Depot Monolith after Injectionof Depot Formulation Precursor Between the Bone and Periostium

A precursor (36% wt PC, 54% wt GDO, and 10% wt EtOH prepared asdescribed in Example 1) was injected by syringe between the bone andperiostium. The composition was observed to spread to fill voids andafter uptake of aqueous fluids formed a monolith that was bioadhesive toboth the bone and periostium.

Example 9 Bioadhesive Spray of Depot Precursor Formulation

A pump spray bottle was found to be a convenient way to apply theformulation topically, e.g. to the skin or the oral mucosa.

A depot precursor formulation prepared as in Example 1 (36% wt PC, 54%wt GDO, and 10% wt EtOH) was sprayed with a pump spray bottle onto theskin and oral mucosa. A film with solid mechanical properties formedshortly after application.

Example 10 Robustness of a Topical Film

After applying the depot precursor formulation, as described in Example22, (36% wt PC, 54% wt GDO, and 10% wt EtOH) to the skin, the appliedformulation was exposed to flushing water (10 L/min) for 10 minutes. Theformulation showed excellent bioadhesive properties and resistanceagainst rinsing and no loss of the formulation could be discerned.

Example 11 Formation of Cubic Phase with Solid Properties after Exposureof Depot Precursor Formulation to Air

After exposing a depot precursor formulation prepared as described inExample 1 (36% wt PC, 54% wt GDO, and 10% wt EtOH) to air (RT, relativehumidity 40%) for at least 3 hours, a solid cubic phase was formed. Thisformation of a cubic phase structure demonstrates that a topical filmwill acquire bulk non-lamellar depot properties after applicationwithout the need for direct exposure to excess aqueous fluid.

Example 12 Oral Cavity Spray Depot Composition

To be suitable as a topical depot system in the oral cavity themechanical properties of the system was adjusted by decreasing thePC/GDO ratio.

A mixture containing PC/GDO/EtOH (27/63/10) was prepared according toExample 1. A drop of patent blue was added to visualize the formulationafter application. About 300 μl of the formulation was sprayed into theoral cavity with pump spray bottle. Shortly after application theformulation viscosified/solidified since it underwent a phasetransformation by uptake of aqueous fluid (saliva) and loss of solvent(EtOH). The formulation had excellent bioadhesion to keritinizedsurfaces such as the hard palate and the gum. Here the film lasted forseveral hours despite saliva secretion and mechanical wear by thetongue. At soft mucosal surfaces the duration was much shorter(minutes).

Example 13 Oral Cavity Liquid Depot Composition

To be suitable for application with a pipette to the oral cavity thesolidification/viscosification of the formulation has to be delayedrelative to the spray formulation. This is to allow the formulation tobe conveniently distributed with the tongue to a thin film in the oralcavity after application.

Propylene glycol (PG) and EtOH were added to a formulation prepared asin Example 1, to the final composition PC/GDO/EtOH/PG (24/56/10/10). 300μl of the formulation was conveniently applied with a pipette to theoral cavity and distributed with the tongue to a thin film in the oralcavity. After about 20 seconds the viscosification of the formulationstarted since it underwent a phase transformation by uptake of aqueousfluid (saliva) and loss of solvent (EtOH and PG). After about one minutethe solidification/viscosification appeared to be finished. Theformulation had excellent bioadhesion to keritinized surfaces such asthe hard palate and the gum. Here the film lasted for several hoursdespite saliva secretion and mechanical wear by the tongue. At softmucosal surfaces the duration was much shorter (minutes).

Example 14 Compositions Containing PC and Tocopherol

Depot precursor formulations were prepared with several differentPC/α-tocopherol compositions using the method of Example 1 (PC was firstdissolved in the appropriate amount of EtOH and thereafter α-tocopherolwas added to give clear homogenous solutions).

Each formulation was injected in a vial and equilibrated with excesswater. The phase behaviour was evaluated visually and between crossedpolarizes at 25° C. Results are presented in Table 8.

TABLE 8 α- tocopherol PC Ethanol Phase in excess H₂O 2.25 g 2.25 g 0.5 gH_(II)  2.7 g  1.8 g 0.5 g H_(II)/I₂ 3.15 g 1.35 g 0.5 g I₂  3.6 g  0.9g 0.5 g I₂/L₂

Example 15 In Vitro Release of Water-Soluble Disodium Fluorescein

A water-soluble colorant, disodium fluorescein (Fluo), was dissolved ina formulation containing PC/α-tocopherol/Ethanol (27/63/10 wt %) to aconcentration of 5 mg Fluo/g formulation. When 0.1 g of the formulationwas injected in 2 ml of phosphate buffered saline (PBS) a reversedmicellar (I₂) phase was formed. The absorbency of Fluo released to theaqueous phase was followed at 490 nm over a period of 3 days. Therelease study was performed in a 3 mL vial capped with an aluminiumfully tear off cap at 37° C. The vial was placed on a shaking table at150 rpm.

The release of Fluo from the PC/α-tocopherol formulation (see Table 9)indicates that this (and similar) formulations are promising depotsystems. Furthermore, the absence of a burst effect is noteworthy, andthe release indicates that the substance can be released for severalweeks to months; only about 0.4% of Fluo is released after 3 days.

TABLE 9 % release (37° C.) Formulation 24 h 72 h PC/α-tocopherol/EtOH:<0.1* 0.43 27/63/10 wt % *Release below detection limit of theabsorbance assay

Example 16 Fentanyl Nasal Formulation

Formulations were prepared as in Example 1 by mixing the narcoticanalgesic fentanyl with a mixture of GDO, PC, ethanol and optionally PGin the following proportions.

Formulation Fentanyl PC GDO EtOH PG 1 0.05 34 51 10 5 2 0.05 36 54 10 —3 0.05 42 43 10 5 4 0.05 45 45 10 — 5 0.15 34 51 10 5 6 0.15 36 54 10 —7 0.05 30 45 15 10  8 0.15 30 45 15 10  where EtOH is ethanol, PC isLIPOID S100 soybean phosphatidylcholine, GDO is glycerol dioleate, andPG is propylene glycol

All formulations are low viscosity liquids suitable for administrationby nasal spray, which generate liquid crystalline phase compositionsupon exposure to aqueous conditions.

Example 17 Further Examples of Viscosity in PC/GDO Mixtures on Additionof Co-Solvent

Mixtures of PC/GDO and co-solvent were prepared according to the methodsof Example 1 and Example 3 in the proportions indicated in the tablebelow. The samples were allowed to equilibrate for several days beforeviscosity measurements were performed using a Physica UDS 200 rheometerat 25° C.

PC/GDO EtOH/ Glycerol/ H₂O/ Viscosity/ Sample (wt/wt) wt % wt % wt %mPas 1 50/50 3 — — 1900 2 50/50 5 — — 780 3 50/50 7 — — 430 4 50/50 8 —— 300 5 50/50 10 — — 210 6 50/50 15 — — 100 7 45/55 3 — — 1350 8 45/55 5— — 540 9 45/55 7 — — 320 10 45/55 8 — — 250 11 45/55 10 — — 150 1245/55 15 — — 85 13 40/60 3 — — 740 14 40/60 5 — — 400 15 40/60 7 — — 24016 40/60 8 — — 200 17 40/60 10 — — 130 18 40/60 15 — — 57 19 40/60 — 10— 8 * 10⁶ 20 40/60 — — 3 2.5 * 10⁸   21 40/60 — — 5 4 * 10⁷

This example further illustrates the need for a solvent with viscositylowering properties in order to obtain injectable formulations. Themixtures containing glycerol (sample 19) or water (samples 20 and 21)are too viscous to be injectable at solvent concentrations equivalent tothe samples containing EtOH (compare with samples 13, 14 and 17).

Example 18 Buprenorphine Depot

A mixture of GDO, PC and EtOH was manufactured according to the methoddescribed in Example 1. The opioid buprenorphine was added and theformulation mixed to homogeneity to obtain the following composition:

Buprenorphine GDO PC EtOH 5 wt % 45 wt % 45 wt % 5 wt %

Sterile-filtration was performed by passing the final precursorformulation through a standard sterile filtration membrane (Millex GP0.22 μm).

Example 19 In Vivo Release of Buprenorphine

Three suitable volumes (0.3 mL/kg, 1.0 mL/kg, and 1.5 mL/kg) of thecomposition of Example 18 were injected into 18 male SPF Sprague-Dawleyrats (weighing ca. 300 g). Blood samples were collected pre-dose, 3 hrs,6 hrs, 1 day, 2 days, 7 days, 14 days, 21 days and 28 days after dosing.The plasma concentrations were determined with the aid of a commercialELISA kit adapted for analysis of buprenorphine in rat plasma. Theresults from the three groups (n=6) are shown in FIG. 3, and demonstratethe ability to deliver buprenorphine at target human therapeutic levelsto rats for at least 4 weeks. No obvious adverse side effects were seen.

Example 20 Solubility of Buprenorphine in Depot Precursor Formulations

Buprenorpine solubility in formulation precursors was determined by thefollowing protocol; buprenorphine in excess was added to formulationprecursors and samples were equilibrating by end-over-end mixing in roomtemperature for four days. Excess buprenorphine was removed byfiltration and concentration in precursor formulations determined withHPLC. Formulation precursors in the table below differ by the additionalsolvent (ethanol (EtOH), benzylalcohol (BzOH), polyethyleneglycol 400(PEG400), benzyl benzoate (BzB), and dimethylsulphoxide (DMSO)).

Composition of formulation precursor PC/ GDO/ EtOH/ Additionalbuprenorphine Sample wt % wt % wt % solvent/wt % solubility/wt % 1 47.547.5 5 — 10.4 2 45 45 5 EtOH/5 10.3 3 45 45 5 BzOH/5 9.9 4 45 45 5PEG400/5 10.8 5 45 45 5 BzB/5 11.2 6 45 45 5 DMSO/5 15.2

Example 21 In Vitro Behaviour of Buprenorphine Depot PrecursorFormulations

After injection into excess water or excess saline (0.9% NaCl) a liquidcrystalline phase in the form of a high viscous monolith formed with allformulation precursors described in example 20. In general thetransformation was somewhat slower with additional solvent, whilebuprenorphine appeared not to have a strong influence on the monolithformation.

Example 22 Composition and In Vitro Phase Study

The formulations were manufactured according to the method described inExample 1 with compositions according to Table 2. An active substance(peptide), salmon calcitonin (sCT). was added to each formulation to aconcentration of 500 μg sCT/g formulation. The formulations weredesigned as homogenous suspensions for parenteral administration (mixingrequired shortly prior to use since the drug is not completely dissolvedin the PC/GDO/EtOH system).

The phase study in this example is performed in excess of rat serum at37° C. in order to simulate an in vivo situation. Table 2 shows that thesame phases as those in water are formed (compare Table 1).

TABLE 2 PC GDO OA EtOH Phase in Formulation (wt %) (wt %) (wt %) (wt %)rat serum E 18 72 — 10 L₂ F 36 54 — 10 I₂ G 34 51 5 10 I₂ H 54 36 — 10H₁₁ I 72 18 — 10 H₁₁/L_(α) OA = Oleic Acid

1. A non-liquid crystalline formulation precursor for the in vivogeneration of a liquid crystalline lipid composition for the controlledrelease of at least one opioid bioactive agent following parenteraladministration, said formulation precursor comprising: i) Alow-viscosity, non-liquid crystalline mixture having a viscosity of 1 to1000 mPas at 20° C. and comprising: a) a minimum of 18 wt. % of at leastone neutral diacyl lipid or a mixture of a neutral diacyl lipid and atleast one tocopherol; b) at least one phospholipid; and c) abiocompatible, oxygen containing, low viscosity organic solventcomprising ethanol; and ii) at least one opioid bioactive agentdissolved or dispersed in the low viscosity mixture; wherein thepre-formulation forms, at least one non-lamellar liquid crystallinephase structure in vivo upon contact with an aqueous fluid.
 2. Theformulation precursor as claimed in claim 1 wherein said non-lamellarliquid crystalline phase structure is bioadhesive.
 3. The formulationprecursor as claimed in claim 1 wherein component a) consistsessentially of diacyl glycerols.
 4. The formulation precursor as claimedin claim 1 wherein component a) consists essentially of a mixture ofglycerol dioleate and tocopherol.
 5. The formulation precursor asclaimed in claim 1 wherein component b) is selected fromphosphatidylcholines, phosphatidylethanolamines, phosphatidylserines,phosphatidylinositols and mixtures thereof.
 6. The formulation precursoras claimed in claim 1 having a molecular solution, L₂ and/or L₃ phasestructure.
 7. The formulation precursor as claimed in claim 1 having aratio of a) to b) of between 95:5 and 5:95 by weight.
 8. The formulationprecursor as claimed in claim 1 having 0.5 to 50% component c) by weightof components a)+b)+c).
 9. The formulation precursor as claimed in claim1 additionally comprising up to 10% by weight of a)+b) of a chargedamphiphile.
 10. The formulation precursor as claimed in claim 1 whereinsaid active agent is selected from natural opium alkaloids,semi-synthetic opioids and synthetic opioids.
 11. The formulationprecursor as claimed in claim 10 wherein said synthetic opioid isselected from bezitramide, methadone, LAAM, loperamide, diphenoxylate,buprenorphine and etorphine.
 12. The formulation precursor as claimed inclaim 11 wherein said synthetic opioid is buprenorphine or methadone.13. The formulation precursor as claimed in claim 1 which isadministrable by injection.
 14. The formulation precursor as claimed inclaim 1 which is administrable by spraying, dipping, rinsing,application from a pad or ball roller, painting, dropping, aerosolspraying or pump spraying.
 15. The method of delivery of an opioidbioactive agent to a human or non-human mammalian body, the methodcomprising administering a formulation precursor comprising: i)non-liquid crystalline, low viscosity mixture having a viscosity of 1 to1000 mPas at 20° C. and comprising: a) a minimum of 18 wt. % of acomponent consisting of at least one neutral diacyl lipid or a mixtureof a neutral diacyl lipid and at least one tocopherol; b) at least onephospholipid; and c) at least one biocompatible, oxygen containing, lowviscosity organic solvent; ii) at least one opioid bioactive agentdissolved or dispersed in the low viscosity mixture, whereby saidadministration serves to form at least one non-lamellar liquidcrystalline phase structure in vivo upon, contact with an aqueous fluid.16. A method as claimed in claim 15 wherein said formulation precursoris a formulation precursor as claimed in claim
 1. 17. The method asclaimed in claim 15 wherein said formulation precursor is administeredby a method selected from subcutaneous injection, intramuscularinjection, intra-cavity injection through tissue, intra-cavity injectioninto an open cavity without tissue penetration, spraying, rolling,wiping, dabbing, painting, rinsing, or dropping.
 18. A method for thepreparation of a non-lamellar liquid crystalline composition comprisingexposing a formulation precursor comprising: i) non-liquid crystalline,low viscosity mixture having a viscosity of 1 to 1000 mPas at 20° andcomprising: a) a minimum of 18 wt. % of a component comprising at leastone neutral diacyl lipid or a mixture of a neutral diacyl lipid and atleast one tocopherol; b) at least one phospholipid; and c) at least onebiocompatible, oxygen containing, low viscosity organic solvent; ii) atleast one opioid bioactive agent dissolved or dispersed in the lowviscosity mixture, to an aqueous fluid in vivo.
 19. The method asclaimed in claim 18 wherein said formulation precursor is a formulationprecursor as claimed in claim
 1. 20. A process for the formation of aformulation precursor for the administration of an opioid bioactiveagent to a mammalian subject, said process comprising forming anon-liquid crystalline, low viscosity mixture having a viscosity of 1 to1000 mPas at 20° C. and comprising: a) a minimum of 18 wt. % of acomponent consisting of at least one neutral diacyl lipid or a mixtureof a diacyl lipid and at least one tocopherol; b) at least onephospholipid; c) at least one biocompatible, oxygen containing lowviscosity, organic solvent; and dissolving or dispersing at least oneopioid bioactive agent in the low viscosity mixture, or in at least oneof components a, b or c prior to forming the low viscosity mixture. 21.The process as claimed in claim 20 wherein said formulation precursor isa formulation precursor as claimed in claim
 1. 22. A method of treatmentor prophylaxis of a human or non-human animal subject comprisingadministration of the formulation as claimed in claim
 1. 23. The methodof claim 22 for the treatment of a condition selected from pain,diarrhoea, depression, opioid dependence, opioid addiction, and thesymptoms of opioid withdrawal.
 24. The method of claim 23 forprophylaxis against the symptoms of opioid withdrawal.
 25. The method ofclaim 23 wherein opioid dependence, opioid addiction, and/or thesymptoms of opioid withdrawal result from opioid abuse.